HEMA2 Lec 1st Shift Reviewer Neutrophilia

Nonmalignant Disorders of • Increase in the number of neutrophils

• Present in some forms of leukemia and
Granulocytes & Monocytes
nonmalignant conditions such as:
Prepared by: C3 o Inflammatory conditions
o Infection
QUANTITATIVE DISORDERS o MPD
• May reflect either a: • Can also be caused by:
o General increase o Physical stimuli (heat or cold)
(leukocytosis) o Surgery
 Neutrophilia o Burns
 Eosinophilia o Stressful activities / vigorous
 Basophilia exercise
 Monocytosis o Nausea
o General decrease o Vomiting
(leukocytopenia) o Certain drugs and hormones
 Neutropenia o Acute hemorrhage
 Eosinopenia o CML
 Basopenia o Leukemoid reaction
 Monocytopenia
Eosinophilia
Leukocytosis • Increased numbers of eosinophils
• Increase in the concentration or • Caused by:
percentage of any of the leukocytes in o Active allergic disorders
the peripheral blood  Asthma
o Increase in neutrophils is the  Hay fever
most frequent cause of o Dermatoses
nonmalignant increases in the o Nonparasitic infections
total leukocyte count o Some forms of leukemia
• Nonmalignant leukocytosis can be o Parasitic infections
caused by various conditions in several (nonprotozoan)
general categories: • Vacuolization and degranulation can be
o Increased movement of observed
immature cells out of the bone • Charcot-Leyden crystals can be found in
marrow’s proliferative the tissues, exudates, sputum, and stool
compartment of patients
o Increased mobilization of cells • Significant eosinophilia (20% to 70% or
from the maturation-storage higher) is most frequently seen in:
compartment of the bone o Trichinosis
marrow to the peripheral blood o Strongyloidiasis
o Increased movement of mature o Hookworm infection
cells from the marginating pool o Filariasis
to the circulating pool o Schistosomiasis
o Decreased movement of mature o Fasciolopsiasis
cells from the circulation into the • Moderate eosinophilia (6% to 20%) is
tissues related to:
o Trichuriasis
o Ascariasis
o Paragonimiasis
o Taeniasis
o Eosinophilic meningitis

TRIPLE C NOTES 1
Basophilia
• Increase in basophils exceeding 0.075 x
109/L caused by hormones
• Can be seen in:
o Ulcerative colitis
o Hyperlipidemia
o Smallpox and chickenpox
o Chronic sinusitis
o CML
o Polycythemia vera
o Radiation exposure
Monocytosis
• Significant absolute increase in
circulating monocytes
• Disorders commonly associated include:
o Infections
 Tuberculosis
 Bacterial endocarditis
o Fever of unknown origin
o Inflammatory bowel disease
o Rheumatoid arthritis
o Hematological disorders
 Hemolytic anemia
Leukocytopenia
• Decrease in the concentration or
percentage of any of the leukocytes in
the peripheral blood
• Infiltration of malignant cells
Neutropenia
• Reduction in the number of circulating
neutrophils
• Caused by:
o Underproduction of cells caused
by bone marrow injury or
infiltration of the marrow by
malignant cells
o Nutritional deficiencies
 Starvation
 Anorexia nervosa
o Cyclic neutropenia
o Increased destruction or
utilization of neutrophils
o Entrapment in the spleen
• Most transient neutropenias in children
are acquired disorders, and viral
infections are a common cause
• Congenital neutropenia can be caused
by:
o Agranulocytosis of the
Kostmann type
o Myelokathexis
o Reticular dysgenesis
o Type IB glycogen storage
disease
o Transcobalamin-II deficiency
Eosinopenia
• Rare, stress-related condition of
decreased eosinophils
• Frequently related to:
o Action of glucocorticosteroid
hormones
o Aftermath of acute bacterial or
viral inflammation
Basopenia
• Decreased number of basophils
• Can be caused by:
o Hormones
 Corticotropin
 Progesterone
o Occurring at time of ovulation
o Thyrotoxicosis
Monocytopenia
• Decreased number of monocytes
• No conditions are known to be related to
a decrease in monocytes
MORPHOLOGICAL ABNORMALITIES
OF MATURE GRANULOCYTES (PART
OF QUALITATIVE DISORDERS)
• May be categorized as either:
o Nuclear Anomalies
 Hypersegmentation
 Pelger-Huët Anomaly
o Cytoplasmic Anomalies
 Toxic Granulation
 Döhle Bodies
 May-Hegglin Anomaly
 Chédiak-Higashi
Syndrome
 Alder-Reilly Inclusions
 Ehrlichia
TRIPLE C NOTES 2
Hypersegmentation • Heavy chromatin clumping distinguishes
• Most frequently seen in segmented Pelger-Huët anomaly from the left shift
neutrophils with more than five lobes or of infection
nuclear segments • Defect in maturation of Lamin B receptor
• Caused by abnormal maturation (LBR)
• Frequently associated with: o Integral protein in the NM
o Vitamin B12 deficiency o Laminopathy
o Folic acid deficiency  Muscular dystrophy
o Chronic infections  Premature aging
o Myelodysplastic syndromes • Can be categorized as:
o Hereditary hypersegmentatoin o Acquired (Pseudo Anomaly)
o Long-term infections  Drug induced
• Exists along with abnormally enlarged,  May occur in a
oval-shaped erythrocytes (megaloblastic maturational arrest
anemia) associated with some
• Pseudohypersegmentation may be seen acute infections
in old segmented neutrophils  50% affected PMN
• May either be: o Inherited
o Acquired (in megaloblastic  Usual occurrence
erythropoiesis)  80% affected; no other
o Inherited (Undritz Anomaly) accompanying
abnormalities
• May either be:
o Heterozygous inherited
disorder (Pince-Nez)
 Bilobed or dumbbell-
shaped nucleus
 Clumped
 Coarse chromatin
 Normal cytoplasmic
granules
o Homozygous inherited
disorder (Stodtmeister)
 Round or oval nuclei
 Dense clumped coarse
Figure 1. Hypersegmentation. Neutrophil has six or
chromatin
more nuclear lobes; eosinophil has greater than four  Normal cytoplasmic
lobes. granules

Pelger-Huët Anomaly
• Genetically autosomal dominant
disorder that produces
hyposegmentation of many of the
mature neutrophils
o Indicates failure of neutrophil to
segment properly
• Although segments fail to lobulate
normally, chromatin clumping and
cytoplasmic maturation are normal

TRIPLE C NOTES 3
Figure 2A & 2B. Pelger-Huët Anomaly showing Figure 3. Toxic granulation. Heavy, coarse, dark-blue
abnormal segmentation of mature neutrophils. (A) primary cytoplasmic granules with strong peroxidase
Stodtmeister; (B) Pince-Nez. activity.

Toxic Granulation Döhle Bodies

• Prominent dark granulation, either fine • Also called Döhle Amato bodies
or heavy, observed in: • Seen as single or multiple, light-blue-
o Band neutrophils staining inclusions on Wright-stained
o Segmented neutrophils blood smears
o Monocytes • Seen near the periphery of the
• Toxic granules are azurophilic (primary) cytoplasm
granules that are peroxidase-positive • Predominantly neutrophils although they
o May represent the precipitation may also be seen in monocytes or
of ribosomal protein (RNA) lymphocytes
caused by metabolic toxicity • Represent aggregates of rough
within the cells (increased ALP endoplasmic reticulum (RNA)
activation) • Caused by localized failure of
• Most frequently associated with: cytoplasmic maturity
o Infectious states • Associated with:
o Burns o Viral infections
o Malignant disorders o Burns
o Result of drug therapy o Certain drugs
o Acute infection o Cancer
o Cancer o Aplastic anemia
o Pregnancy o Pregnancy
o Aplastic anemia o Poisoning
o Drug poisoning o Following chemotherapy
o Growth factor therapy o Myelodysplastic syndromes
o Inflammation (often seen in the degranulated
segmented cells)
o Growth factor therapy
o May-Hegglin anomaly

TRIPLE C NOTES 4
 Chédiak-Steinbrinck-Higashi Syndrome
• Rare hereditary disease (autosomal
recessive trait) of granule production
• Most serious and most fatal but rare
o Primarily seen in children and
young adults
• Affects all leukocytes as well as cells in
other organs like in the skin and eyes
• Gigantic, peroxidase-positive deposits
representing abnormal lysosomal
development
o Seen from those with both
recessive genes)
Figure 4. Döhle Body. Round or rod-shaped, light- o Lymphocytes show an
blue cytoplasmic inclusions, often located near cell impairment of both antibody-
membrane. Inclusions represent ribosomes or rough dependent and NK cell-
endoplasmic reticulum.
mediated cytotoxicity
• Very large reddish purple or greenish-
May-Hegglin Anomaly
gray granules
• Inherited, autosomal-dominant disorder
• Abnormal fusion of primary and
• Large, blue, crescent-shaped
secondary specific cytoplasmic granules
cytoplasmic inclusions (Döhle body-like
produce the giant granules
inclusions)
• PMN become less chemotactic due to
• Ribosomal in origin
membrane receptor defect
• Presence of enlarged, bizarre platelets
• Progress from lymphadenopathy to
• Present in neutrophils, eosinophils, and hepatosplenomegaly to death
monocytes
• Clinical conditions associated:
• Bleeding disorder is due to platelet o Bleeding problems
deficiency, resulting to bleeding o Susceptible to bacterial
tendencies infections
o Genetic disorder in MYH9-gene o Albinism
(Non-Muscle Myosin Heavy o Silvery hair
Chain 9 gene from MYHIIA) o Photophobia
o Randomly placed rods o Progressive neurodysfunction
o Döhle body-like inclusions o Neutropenia
o Thrombocytopenia
o Enlarged lymph nodes
o Fever
• Lab features:
o White Blood Cells
 Typical count of 1-3 x
109/L
 Giant gray-green
peroxidase positive
bodies are found in the
cytoplasm of leukocytes
 Neutropenia
o Red Blood Cells
 Normal
Figure 5. May-Hegglin inclusions. Notice the large o Coagulation studies
blue inclusions that are ribosomal in origin.  Bleeding time abnormal

TRIPLE C NOTES 5
 o Platelets • Coarse blue-black granulations (Rodak)
 Thrombocytopenia or purple-red particles (Turgeon)
 Aggregation is o Metachromatic granules take
abnormal color difference from stain used
o Bone Marrow • Seen in:
 The abnormal granules o Hurler’s Syndrome
from precursor vacuoles o Hunter’s Syndrome
undergo fusion o San Fillipo Syndrome
o Schele’s Syndrome
o Marotaeaux-Lamy type of
genetic mucopolysaccharides
• Deficiency of lysosomal enzymes that
breakdown mucopolysaccharides
• Incomplete degradation on protein-
carbohydrate complexes

Table 1. Clinical conditions affecting

mucopolysaccharides.
Syndrome Enzyme Substance
Deficient Stored
Hurler’s α-L-iduronidase MPS I
Hunter’s Iduronidase MPS II
sulfatase
Figure 6. Chédiak-Higashi Syndrome in a peripheral San Fillipo’s Form A: Heparin MPS III
blood smear. Neutrophils display impaired chemotaxis N-sulfatase
and delayed killing of ingested bacteria.
Form B: MPS IV
N-acetyl-α-
glucosaminidase
Schele’s α-L-iduronidase MPS V

Figure 7. Chédiak-Higashi Syndrome in a bone

marrow smear.

Alder-Reilly Inclusions Figure 8. Alder-Reilly bodies. These are dense blue

• Primarily seen in neutrophils, (or purple-red) cytoplasmic granules consisting of
eosinophils, and basophils stored mucopolysaccharides and sphingomyelin.
o Severe forms are also Nevertheless, they still exhibit normal maturation.
occasionally seen in monocytes
and lymphocytes
• Inherited condition (autosomal
recessive)

TRIPLE C NOTES 6
Myelokathexis Necrobiotic PMN
• Congenital disorder • Considered to be “dead” in segmented
• Inability to release mature granulocytes PMN
into the blood • Caused by condensation of nuclear
• Characterized by neutropenia with chromatin
hypersegmented PMN • Pyknotic nucleus
o Pyknotic nuclei (compact, dying) • Solid structureless mass with no
o Long intrasegmental filament patterns
• Bone marrow hyperplasia • Seen in:
• Apoptosis of granulocyte precursor o Bacterial infection
occurs o Drug intoxication
o Chemotherapy
o Poorly preserved specimen

Figure 9. Myelokathexis in WHIM (Warts, Figure 11. Necrobiotic PMN. Nuclei is degraded to
Hypogammaglobulinemia, Immunodeficiency, and small, round, pyknotic, featureless droplets with pale
Myelokathexis) Syndrome. Bone marrow aspirate or non-granular cytoplasm.
smear shows neutrophil with long, thin, filamentous
strands connecting nuclear lobes. Cytoplasmic Vacuolization
• Primarily affect PMN
Alius-Grignaschi Syndrome • Degenerating cytoplasm acquired holes
• Barr Bodies Syndrome o Vacuoles appear as clear
o Barr Bodies, sex chromatin unstained circular areas in the
bodies which are drumstick, cytoplasm
racket, or sessile nodule in • Undergo acute phagocytosis
appearance • Show an increase in lysosomal activities
• Affects PMN o Phagosome will fuse with
• Nuclear appendages derived from lysosome, forming
inactivated second X chromosome phagolysosome
• 2-3% (6 out of 500) neutrophils in • Seen in:
females are affected o Septicemia
• Round projection attacked by fine strand o Severe infections
of chromatin o Burns
o Nuclear sexing of PMN o Pregnancy
o Cancer
o Aplastic anemia
o Toxic states

TRIPLE C NOTES 7

Figure 12. Cytoplasmic vacuolization. Vacuoles
represent end stage of digestion of phagocytosed
material or fat or other substances.
Jordan’s Anomaly
• Persistent fat-containing vacuoles are
seen in the protoplasm of granulocytes,
monocytes, and occasional lymphocytes
• Seen among people suffering:
o Muscular dystrophy
(degenerative progressive
disorder)
o Ichythyosis
o Storage diseases
Figure 13. Jordan’s anomaly. Many vacuoles are
seen in the cytoplasm of granulocytes.
Lupus Erythematosus (LE) Cell
• Affects PMN, monocyte, and eosinophil
• Presence of ANA (Antinuclear Antigen)
o LE Factor
• Collagen disorder; can cause
rheumatoid arthritism
• Depolymerization of nuclear chromatin
transforms into homogenous round body
• Body acquires chemotactic property and
attract phagocytes
• Morphological features include:
o Nucleus of phagocytic cell is
pushed to the periphery
o Engulfed homogeneous body
occupies central portion
o Typical rosette formation
consisting of homogenous
round body surrounded by
would be phagocytes
• Attributed to Systemic Lupus
Erythematosus (SLE), a decreased
cellular immunity disorder
o Circulating immune complexes
may cause tissue injury in many
organ systems
• Back then, specimens use clotted blood
(no anticoagulant)
o Mush clot via mortar & pestle
o Centrifuge mushed blood
o Prepare smear from buffy coat
o Stain via differential count
smears
o Find LE cell
• Now detected via serology
Figure 14. LE cell. Large, spherical body in cytoplasm
is homogeneous, has no nuclear structure, and stains
pale purple; nucleus of cell is pushed to periphery and
appears to wrap around cytoplasmic inclusion.
TRIPLE C NOTES 8
 Auer Rods
• Affects myeloblasts, monoblasts, and
promyelocytes
• Red to reddish-purple rods with spindle-
shaped bodies
o Owes to high peroxidase activity
• Faggot Cell
o Promyelocyte with Auer Bodies
o Hypergranular variant in Acute
Promyelocytic Leukemia (APL)
(M3)
• Clinically associated with:
Figure 15. Systemic lupus erythematosus in a buffy
coat smear. o Acute Lymphoblastic Leukemia
(ALL)
Nucleophagocytosis o Acute Myelocytic Leukemia
• Affects monocytes and lymphocytes  Without maturation (M1)
(FAB)
• Also called Tart Cell Formation
o Monocyte engulfing the nucleus  With maturation (M2)
or the entire cell of a lymphocyte (FAB)
o Acute Myelomonocytic
• Morphology may often be confused with
Leukemia (M4) (FAB)
an LE cell
o APL (M3) (FAB)
• Pathology is connected to adverse drug
o Erythroleukemia (M6a) (FAB)
reactions or to chemicals
o Acute Myelocytic Leukemia with
multilineage dysplasia
Erythrophagocytosis o Chronic myelocytic leukemia in
• Affects monocytes and red blood cells blastic transformation
• Condition in macrophages engulf the o AML with t(8;21) (WHO)
abnormal RBCs o AML with t(15;17) (WHO)
• Clinically associated with: o AML with inv 16 or t(16;16)
o Autoimmune hemolytic anemia (WHO)
o ABO or Rh incompatibility
• Can cause HDN (Hemolytic Disease of
the Newborn)

Figure 18. Auer rods. They appear as reddish-purple,

rod-shaped cytoplasmic inclusions with alignment of
primary granules.

Figure 16. Erythrophagocytosis. Macrophages or

monocytes engulf the abnormal RBC.

TRIPLE C NOTES 9
OTHER QUALITATIVE DISORDERS • Predisposition to infections and
A. Defective Locomotion and formulation of granulomas during
Chemotaxis chronic inflammatory reactions
a. Locomotion • Characteristic features include:
• Corticosteroids o Accumulation of H2O2 in
• Lazy leukocyte lysosomes
syndrome o Catalase-positive organisms
b. Chemotaxis replicate intracellularly
• Diabetes mellitus • Clinically correlated to recurrent
• Chédiak-Higashi infections with catalase-positive
anomaly organisms (Gram-negative enteric
• Sepsis bacteria and staphylococci)
• Hyperimmunoglobuli-
nemia E (Job
Syndrome)
B. Defects in Microbicidal Activity
a. CGD
b. MPO deficiency
c. Lactoferrin deficiency

Lazy Leukocyte Syndrome

• Syndrome caused by loss of
chemotactic function of neutrophils
• Affects neutrophil actin and myosin
filaments Figure 19. Chronic granulomatous disease. Clinical
• Characterized by neutropenia features include recurrent bacterial infections during
• Neutrophils fail to migrate at site of the first 12 months of life, lymphadenitis, deep tissue
inflammation infections, infected eczema rash, organomegaly, etc.
Hyperimmunoglobulinemia E (Job
Myeloperoxidase (MPO) Deficiency
Syndrome)
• Observed in PMN and monocyte
• Also called Hyper-IgE Syndrome (HIES)
• Mutation in MPO gene
• Dysregulation of cytokine production
• Peroxidase deficient cells demonstrate
• Poor directional mobility of neutrophils
lack of activity with special peroxidase
• High levels of IgE skeletal abnormalities
stain
with recurrent severe bacterial infection
• Most common abnormality
• Mild symptoms
Chronic Granulomatous Disease (CGD)
• Inherited
• X-linked recessive gene (60-65%);
• Acquired
autosomal recessive gene (35-40%)
o Leukemia (untreated)
o Sex-linked = cytochrome b
 AML
defect
 CML
o Autosomal recessive trait =
 Myelodysplastic
NADPH oxidase defect
Syndrome (MDS)
• Show decrease in protein making up
NADPH oxidase
• Phagocytes cannot produce superoxide Leukocyte Adhesion Deficiency (LAD)
and reactive O2 • Autosomal recessive trait
o Caused by failure in the • Absence of integrin (leukocyte cell-
activation of the respiratory surface adhesion proteins)
burst

TRIPLE C NOTES 10
 • Clinically associated with:
o Bacterial and fungal infections
o Diapedesis manner of
movement
o Escape from intact skin
o Gene mutation and cell
adhesion molecules
o Integrins and selectins
o Neutrophils and monocytes fail
to adhere to endothelial cells
and migrate to tissues

LAD I
• β2 integrin subunits (CD11 / CD18) Figure 20. Gaucher disease. Pathological
• decrease or defect in β2 accumulation of glucocerebroside in macrophages of
lymphoid tissue, spleen, liver, and bone marrow.
LAD II
• Faulty ligand for selectin impaired pus Niemann-Pick Disease
formation • Autosomal recessive inherited disorder
• Deficiency in H Blood antigen • Similar to Gaucher disease
• May cause mental retardation and • Represents deficiency of the enzyme
growth defects that normally cleaves phosphoryl choline
from its parent sphingolipid,
LAD III sphingomyelin
• Mildest case of LAD • Pick cell is similar in appearance to the
• KINDLIN 3 (protein that binds to β2 Gaucher cell; however, the cytoplasm of
integrin) the cell is foamy in appearance
• Glanzmann thrombasthemia like
bleeding problems

MONOCYTE-MACROPHAGE
DISORDERS

Gaucher Disease
• Disturbance in cellular lipid metabolism
• Frequently discovered in children
• Represents a deficiency of β-
glucocerebrosindase
o Enzyme that normally splits
Figure 21. Niemann-Pick disease. Pathological
glucose from glucosylceramide
accumulation of sphingomyelin in macrophages in the
• Macrophage in bone marrow lymphoid system.
o Abundant fibrillar blue-gray
cytoplasm
• Striated or wrinkled onion-like
appearance

TRIPLE C NOTES 11